Highlights from Recent Cancer Literature
Journal: Cancer Research (2014)

Sullivan and colleagues examined circulating tumor cells (CTC) in the blood of 33 patients with glioblastoma (GBM). Thirteen had evidence of CTCs in at least one blood draw. EGFR gene amplification validated GBM origin in CTCs from patients known to have amplification in the primary tumor. Patients with progressive disease tended to show a greater frequency of CTCs compared with patients who had stable disease. GBM xenografts shed CTCs in blood from mice and could be categorized according to mesenchymal versus neural transcriptomal subtype. Relative to tumor cells in situ, CTCs were enriched for mesenchymal markers. Whereas a patient with visceral metastasis from GBM showed only mesenchymal CTCs, CTCs in patients without systemic involvement showed a broader range of heterogeneity. These findings demonstrate methodology to identify CTCs in GBM, and indicate that a substantial proportion of cells found in such patients were enriched for the mesenchymal subtype.Sullivan JP, Nahed BV, Madden MW, Oliveira SM, Springer S, Bhere D, et al. Brain tumor cells in circulation are enriched for mesenchymal gene expression. Cancer Discovery; Published OnlineFirst August 19, 2014; doi:10.1158/2159-8290.CD-14-0471.Wiener and colleagues reveal that expression of PROX1, a transcription factor normally limited to rare mouse intestinal cells, was enhanced in intestinal adenomas. In mouse adenoma and human colorectal cancer (CRC) organoid cultures and in vivo, PROX1 deletion reduced stem cell numbers and inhibited proliferation and tumor growth, attributed to increased annexin A1 and decreased filamin A (an actin binding protein and a prognostic marker). Furthermore, loss of Prox1 inhibited autophagy and hypoxic tumor cell survival in tumor transplants. Ragusa and colleagues identified metastatic CRC stem cells in which high PROX1 expression promoted metabolic adaptation and autophagy-dependent survival. Inhibition of autophagy sensitized PROX1+ cancer cells to metabolic insults and blocked formation of macrometastases. These reports portray PROX1 as an essential regulator of CRC progression and reveal cancer type–specific mechanisms of metastasis targetable with autophagy inhibitors.Wiener Z, Högström J, Hyvönen V, Band AM, Kallio P, Holopainen T, et al. Prox1 promotes expansion of the colorectal cancer stem cell population to fuel tumor growth and ischemia resistance. Cell Rep 2014; 8:1943–56.Ragusa S, Cheng J, Ivanov KI, Zangger N, Ceteci F, Bernier-Latmani J, et al. PROX1 promotes metabolic adaptation and fuels outgrowth of Wnt high metastatic colon cancer cells. Cell Rep 2014; 8:1957–73.Pancreatic ductal adenocarcinoma (PDA) has a dense extracellular matrix that limits drug access. Sherman and colleagues compared the transcriptomes of normal and cancer-associated pancreatic stellate cells (PSC), the latter of which are abundant in tumor stroma. In healthy pancreas, PSCs are quiescent. Upon activation by cytokines, growth factors, oxidative stress, or cancer, the PSCs' transcriptome shows high-level expression of the vitamin D receptor (VDR). Cancer-associated PSCs treated with the vitamin D agonist calcipotriol reverted back to near-quiescent PSCs. Calcipotriol reduced PSC activation in mouse models of pancreatitis, cooperating with gemcitabine in a mouse PDA model (improving survival by 57%), in which calcipotriol monotherapy was ineffective. They conclude that activation of the vitamin D receptor reprograms pancreatic tumor stroma, diminishing its capacity to support tumor growth and increasing access of gemcitabine to the bulk of the tumor.Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 2014;159:80–93.It is currently impossible to determine whether a patient carries dormant or active disseminated residual tumor cells decades after diagnosis. Now Chéry and colleagues have used single cell expression profiling of bone marrow EPCAM+ disseminated tumor cells (DTC) to identify signatures that might distinguish dormant DTCs from those that are proliferating or poised to reignite growth. They compared DTCs from patients with no evidence of disease (NED) for up to 18 years with DTCs from patients with clinically detectable metastatic disease. After eliminating EPCAM+ cells that had an erythroid lineage signature they found that DTCs from NED patients carried a specific signature enriched in genes regulated by the p38 kinase, a pathway found to regulate dormancy but never before linked to human DTC clinical behavior. Identification of this signature is an important step forward as it reveals for the first time markers to pinpoint dormant DTCs or those poised to be activated and it also offers new targets that may be used to eradicate dormant DTCs.Chéry L, Lam H-M, Coleman I, Lakely B, Coleman R, Larson S, et al. Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways. Oncotarget 16 Sept 2014; Epub ahead of print.Zhang and colleagues analyzed 95 human colorectal tumor samples by liquid chromatography–tandem mass spectrometry-based shotgun proteomic analysis identifying 124,823 distinct peptides corresponding to 7,211 genes. Although mRNA and protein abundance were positively correlated, transcript abundance did not predict protein abundance for individual genes. Using TCGA copy number alterations (CNA), cis effects of CNAs on protein abundance were weak, with focal amplifications having the greatest effects. Thus, many CNA-driven mRNA level increases did not show increased protein levels. Amplification of 20q was one exception, associated with global changes in mRNA and protein levels. Using protein abundance as an indicator of oncogenic potential for proteins encoded in the amplicon, three candidates were identified on 20q, HNF4α, TOMM34, and SRC. Moreover, proteomic data identified five major tumor subtypes that overlap with and potentially refine previously described transcriptomic subtypes.Zhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z, et al. NCI CPTAC. Proteogenomic characterization of human colon and rectal cancer. Nature 2014;513:382–7.The addition of imatinib to standard chemotherapy for patients with Philadelphia chromosome– positive (Ph+) acute lymphoblastic leukemia (ALL) has revolutionized the outcome for these patients. Roberts and colleagues characterized the spectrum of kinase-activating genetic alterations in patients with Ph-like ALL. These patients, who lack the BCR–ABL translocation yet have a similar gene expression profile, are typically young adults (25%) and have poor outcome. Among 1,725 patients with ALL, 154 had Ph-like ALL. Subgroups of Ph-like ALL included those with CRLF2 rearrangements, ABL-class fusions, a high frequency of rearrangements activating JAK2 in young adults, and recurrent erythropoietin receptor rearrangements. All of these subgroups exhibited activation of the JAK–STAT pathway. While this study highlights the complexity of Ph-like ALL, the identification of targetable kinase alterations provides new therapeutic avenues.Roberts KG, Li Y, Payne-Turner D, Downing JR, Hunger SP, Willman CL, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med 2014; 371:1005–15.